Dopamine, serotonin and norepinephrine are the three important neurotransmitters in the human brain. The extracellular concentration of these neurotransmitters are regulated by the membrane bound transporters, the dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET) by reuptake of the neurotransmitters from the neuronal cleft.
Dysfunction of the monoamine neurotransmitter function has been implicated in a number of CNS (Central Nervous System) diseases such as depression (see, e.g. Charney et al., J. Clin. Psychiatry, 59, 11-14 (1998); Delgado et al., J. Clin. Psychiatry, 61 (Suppl 6), 7-11 (2000); Ressler et al., Depress. Anxiety, 12 (Suppl 1), 2-19 (2000); Hirschfeld, J. Clin. Psychiatry, 61 (Suppl 6), 4-6 (2000); Prins et al., Expert Opin. Investig. Drugs 20, 1107-1130 (2011)). Selective serotonin reuptake inhibitors (SSRIs) and dual serotonin and norepinephrine reuptake inhibitors (SNRIs) have been widely used as antidepressants. The SSRIs and SNRIs however have slow onset of action and take several weeks of treatment before improvement in symptoms and some inhibitors cause side effects such as insomnia and sexual dysfunction. Moreover, a significant number of patients do not respond to currently available antidepressants.
Reduced levels of endogenous DA, 5-HT and NE have been suggested to play a role in acute and chronic pain at both the spinal and supraspinal levels (Ren et al., Pain 100, 1-6 (2002)). Reuptake inhibitors of these neurotransmitters consequently can attenuate pain by preventing presynaptic uptake of these neurotransmitters leading to sustained activation of the descending pain inhibitory pathways (Zhuo et al., Brain Res. 550, 35-48 (1991)). Pharmacological studies suggest that drugs simultaneously inhibiting reuptake of DA, 5-HT and NE may provide a broader spectrum of pain relief than single or dual acting agents (see Hache et al., Pharmaceuticals, 4, 285-342 (2011)). Indeed studies with the triple reuptake inhibitor bacifacidine have shown that it is efficacious as an antinociceptive agent with antiallodynic and antihyperalgesic activity in acute, persistent and chronic pain models (Basile et al., J. Pharmacol. Exp. Ther. 321, 1208-1225 (2007)), and has been evaluated in clinical trials for the treatment of pain.
Despite the identification of weak partial inhibitors of the dopamine transporter in earlier studies (Ananthan et al., Bioorg. Med. Chem. Lett. 12, 2225-2228 (2002); Rothman et al., Synapse, 43, 268-274 (2002); Pariser et al., J. Pharmacol. Exp. Ther. 326, 286-295 (2008); Rothman et al., J. Pharmacol. Exp. Ther. 329, 718-728 (2009); Zhu et al., Synapse, 65, 1251 (2011)), the compounds that can effectively function as reuptake inhibitors of dopamine, serotonin, and norepinephrine have remained elusive. Thus, there remains a need for reuptake inhibitors selective for all three neurotransmitters. In addition to a favorable balance of inhibition potency among the three transporters, compounds that have submaximal efficacy in inhibiting the reuptake by allosteric or other mechanisms could provide therapeutic advantages over full efficacy inhibitors due to their ability to normalize the neurotransmitter levels depending upon the state of neurotransmitter.